The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation
Year: 2018
Type: article
Abstract: Antigen presentation to T cells in major histocompatibility complex class II (MHC class II) requires the conversion of early endo/phagosomes into lysosomes by a process called maturation. Maturation is driven by the phosphoinositide kinase PIKfyve. Blocking PIKfyve activity by small molecule inhibitors caused a delay in the conversion of phagosomes into lysosomes and in phagosomal acidification, whereas production of reactive oxygen species (ROS) increased. Elevated ROS resulted in reduced activity of cathepsin S and B, but not X, causing a proteolytic defect of MHC class II chaperone invariant chain Ii processing. We developed a novel universal MHC class II presentation assay based on a bio-orthogonal "clickable" antigen and showed that MHC class II presentation was disrupted by the inhibition of PIKfyve, which in turn resulted in reduced activation of CD4 + T cells. Our results demonstrate a key role of PIKfyve in the processing and presentation of antigens, which should be taken into consideration when targeting PIKfyve in autoimmune disease and cancer.
Source: iScience
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,240
Funders: Human Frontier Science Program, Stanford University, European Commission, Radboud Universiteit, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Radboud Universitair Medisch Centrum, National Institutes of Health, European Research Council, National Institute of General Medical Sciences
Awards: G1366000929, Metabolic Engineering with Bioorthogonal Chemical Reporters, G3410208876, TLR-induced rerouting of intracellular membrane trafficking during antigen cross-presentation., G6377370000, Trans-membrane proteins: an overlooked source of antigens., G7010378412, G7446833893, G9000054226, G93366558, G96092171
OpenAlex ID: W2905652762